Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1

ABSTRACT

The present invention relates to using a compound having the formula (I) wherein T is I) thienyl, which optionally is substituted with halogen, or II) phenyl optionally substituted with halogen and/or C 1-6 -alkyl; E is a bond, —CH 2 — or —CO—; L is a bond, —CH 2 —, —CHR 4 — or —NR 3 —; R 3  is H, C 1-6 -alkyl, C 1-6 -acyl or —COR 4 ; R 4  is morpholino or C 1-6 -amido; R 6  and R 7  are independently hydrogen or C 1-6 -alkyl; and R 8  and R 9  are independently hydrogen or C 1-6 -alkyl, as well as pharmaceutically acceptable salts, hydrates and solvates thereof, in the manufacture of a medicament for the treatment or prevention of diabetes, syndrome X, obesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, osteoporosis, tuberculosis, dementia, depression, virus diseases and inflammatory disorders.

TECHNICAL FIELD

The present invention relates to novel compounds, to pharmaceuticalcompositions comprising the compounds, to processes for theirpreparation, as well as to the use of the compounds in medicine and forthe preparation of a medicament which acts on the human11-βhydroxysteroid dehydrogenase type 1 enzyme (11βHSD1).

BACKGROUND ART

1. Glucorticoids, Diabetes and Hepatic Glucose Production

It has been known for more than half a century that glucocorticoids havea central role in diabetes, e.g. the removal of the pituitary or theadrenal gland from a diabetic animal alleviates the most severe symptomsof diabetes and lowers the concentration of glucose in the blood (Long,C. D. and F. D. W. Leukins (1936). Exp. Med. 63: 465-490; Houssay, B. A.(1942) Endocrinology 30: 884-892). It is also well established thatglucocorticoids enable the effect of glucagon on the liver.

The role of 11βHSD1 as an important regulator of local glucocorticoideffect and thus of hepatic glucose production is well substantiated (seee.g. Jamieson et al. (2000) J. Endocrinol. 165: p. 685-692). The hepaticinsulin sensitivity was improved in healthy human volunteers treatedwith the non-specific 11βHSD1 inhibitor carbenoxolone (Walker, B. R. etal. (1995) J. Clin. Endocrinol. Metab. 80:3155-3159). Furthermore, theexpected mechanism has been established by different experiments withmice and rats. These studies showed that the mRNA levels and activitiesof two key-enzymes in hepatic glucose production were reduced, namely:the rate-limiting enzyme in gluconeogenesis, phosphoenolpyruvatecarboxykinase (PEPCK), and glucose-6-phosphatase (G6Pase) catalyzing thelast common step of gluconeogenesis and glycogenolysis. Finally, theblood glucose level and hepatic glucose production is reduced in micehaving the 11βHSD1 gene knocked-out Data from this model also confirmthat inhibition of 11βHSD1 will not cause hypoglycemia, as predictedsince the basal levels of PEPCK and G6Pase are regulated independentlyof glucocorticoids (Kotelevtsev, Y. et al., (1997) Proc. Natl. Acad.Sci. USA 94: 14924-14929).

2. Possible Reduction of Obesity and Obesity Related Cardiovascular RiskFactors

Obesity is an important factor in syndrome X as well as in the majority(>80%) of type 2 diabetic, and omental fat appears to be of centralimportance. Abdominal obesity is closely associated with glucoseintolerance, hyperinsulinemia, hypertriglyceridemia, and other factorsof the so-called syndrome X (e.g. raised blood pressure, decreasedlevels of HDL and increased levels of VLDL) (Montague & O'Rahilly,Diabetes 49: 883-888, 2000). Inhibition of the enzyme in pre-adipocytes(stromal cells) has been shown to decrease the rate of differentiationinto adipocytes. This is predicted to result in diminished expansion(possibly reduction) of the omental fat depot, i.e. reduced centralobesity (Bujalska, I. J., S. Kumar, and P. M. Stewart (1997) Lancet 349:1210-1213).

Inhibition of 11βHSD1 in mature adipocytes is expected to attenuatesecretion of the plasminogen activator inhibitor 1 (PAI-1)—anindependent cardiovascular risk factor (Halleux, C. M. et al. (1999) J.Clin. Endocrinol. Metab. 84: 4097-4105). Furthermore, there is a clearcorrelation between glucocorticoid “activity” and cardiovascular riskfactore suggesting that a reduction of the glucocorticoid effects wouldbe beneficial (Walker, B. R. et al. (1998) Hypertension 31: 891-895;Fraser, R. et al. (1999) Hypertension 33: 1364-1368).

Adrenalectomy attenuates the effect of fasting to increase both foodintake and hypothalamic neuropeptide Y expression. This supports therole of glucocorticoids in promoting food intake and suggests thatinhibition of 11βHSD1 in the brain might increase satiety and thereforereduce food intake (Woods, S. C. et al. (1998) Science, 280: 1378-1383).

3. Possible Beneficial Effect on the Pancreas

Inhibition of 11βHSD1 in isolated murine pancreatic β-cells improves theglucose-stimulated insulin secretion (Davani, B. et al. (2000) J. Biol.Chem. 2000 Nov. 10; 275(45): 34841-4). Glucocorticoids were previouslyknown to reduce pancreatic insulin release in vivo (Billaudel, B. and B.C. J. Sutter (1979) Horm. Metab. Res. 11: 555-560). Thus, inhibition of11βHSD1 is predicted to yield other beneficial effects for diabetestreatment, besides effects on liver and fat.

4. Possible Beneficial Effects on Cognition and Dementia

Stress and glucocorticoids influence cognitive function (de Quervain D.J.-F., B. Roozendaal, and J. L. McGaugh (1998) Nature 394: 787-790). Theenzyme 11βHSD1 controls the level of glucocorticoid action in the brainand thus contributes to neurotoxicity (Rajan, V., C. R. W. Edwards, andJ. R. Seckl, J. (1996) Neuroscience 16: 65-70; Seckl, J. R., Front(2000) Neuroendocrinol. 18: 49-99). Unpublished results indicatesignificant memory improvement in rats treated with a non-specific11βHSD1 inhibitor (J. Seckl, personal comnmunication). Based the aboveand on the known effects of glucocorticoids in the brain, it may also besuggested that inhibiting 11βHSD1 in the brain may result in reducedanxiety (Tronche, F. et al. (1999) Nature Genetics 23: 99-103). Thus,taken together, the hypothesis is that inhibition of 11βHSD1 in thehuman brain would prevent reactivation of cortisone into cortisol andprotect against deleterious glucocorticoid-mediated effects on neuronalsurvival and other aspects of neuronal function, including cognitiveimpairment, depression, and increased appetite (previous section).

5. Possible Use of Immuno-Modulation Using 11βHSD1 Inhibitors

The general perception is that glucocorticoids suppress the immunesystem. But in fact there is a dynamic interaction between the immunesystem and the HPA (hypothalamo-pituitary-adrenal) axis (Rook, G. A. W.(1999) Balliér's Clin. Endocrinol. Metab. 13: 576-581). The balancebetween the cell-mediated response and humoral responses is modulated byglucocorticoids. A high glucocorticoid activity, such as at a state ofstress, is associated with a humoral response. Thus, inhibition of theenzyme 11βHSD1 has been suggested as a means of shifting the responsetowards a cell-based reaction.

In certain disease states, including tuberculosis, lepra and-psoriasisthe immune reaction is normaly biased towards a humoral response when infact the appropriate response would be cell based. Temporal inhibitionof 11βHSD1, local or systemic, might be used to push the immune systeminto the appropriate response (Mason, D. (1991) Immunology Today 12:57-60; Rook et al, supra).

An analogous use of 11βHSD1 inhibition, in this case temporal would beto booster the immune response in association with immunization toensure that a cell based response would be obtained, when desired.

6. Reduction of Intraocular Pressure

Recent data suggest that the levels of the glucocorticoid targetreceptors and the 11βHSD enzymes determines the susceptibility toglaucoma (Stokes, J. et al. (2000) Invest. Ophthalmol. 41: 1629-1638).Further, inhibition of 11βHSD1 was recently presented as a novelapproach to lower the intraocular pressure (Walker E. A. et al, posterP3-698 at the Endocrine society meeting Jun. 12-15, 1999, San Diego).Ingestion of carbenoxolone, a non-specific inhibitor of 11βHSD1, wasshown to reduce the intraocular pressure by 20% in normal subjects. Inthe eye, expression of 11βHSD1 is confined to basal cells of the cornealepithelium and the non-pigmented epithelialium of the cornea (the siteof aqueous production), to ciliary muscle and to the sphincter anddilator muscles of the iris. In contrast, the distant isoenzyme 11βHSD2is highly expressed in the non-pigmented ciliary epithelium and cornealendothelium. None of the enzymes is found at the trabecular meshwork,the site of drainage. Thus, 11βHSD1 is suggested to have a role inaqueous production, rather than drainage, but it is presently unknown ifthis is by interfering with activation of the glucocorticoid or themineralocorticoid receptor, or both.

7. Reduced Osteoporosis

Glucocorticoids have an essential role in skeletal development andfunction but are detrimental in excess. Glucocorticoid-induced bone lossis derived, at least in part, via inhibition of bone formation, whichincludes suppression of osteoblast proliferation and collagen synthesis(Kim, C. H., S. L. Cheng, and G. S. Kim (1999) J. Endocrinol. 162:371-379). The negative effect on bone nodule formation could be blockedby the non-specific inhibitor carbenoxolone suggesting an important roleof 11βHSD1 in the glucocorticoid effect (Bellows, C. G., A. Ciaccia, andJ. N. M. Heersche, (1998) Bone 23: 119-125). Other data suggest a roleof 11βHSD1 in providing sufficiently high levels of activeglucocorticoid in osteoclasts, and thus in augmenting bone resorption(Cooper, M. S. et al. (2000) Bone 27: 375-381). Taken together, thesedifferent data suggest that inhibition of 11βHSD1 may have beneficialeffects against osteoporosis by more than one mechanism working inparallel.

WO 99/65884 discloses carbon subtituted aminothiazole inhibitors ofcyclin dependent kinases. These compounds may e.g. be used againstcancer, inflammation and arthritis. U.S. Pat. No. 5,856,347 discloses anantibacterial preparation or bactericide comprising 2-aminothiazolederivative and/or salt thereof. Further, U.S. Pat. No. 5,403,857discloses benzenesulfonamide derivatives having 5-lipoxygenaseinhibitory activity. Additionally, tetrahydrothiazolo[5,4-c]pyridinesare disclosed in: Analgesic tetrahydrothiazolo[5,4-c]pyridines. Fr.Addn. (1969), 18 pp, Addn to Fr. 1498465. CODEN: FAXXA3; FR 9412319690704 CAN 72:100685 AN 1970:100685 CAPLUS and4,5,6,7-Tetrahydrothiazolo[5,4-c]pyridines. Neth. Appl. (1967), 39 pp.CODEN: NAXXAN NL 6610324 19670124 CAN 68:49593, AN 1968: 49593 CAPLUS.

FR 2384498 discloses thiazolo-benzenesulfonamides which showantibacterial, antifungal and hypoglycaemic properties. WO99/28306 andEP 0 819 681 A2 relate to thiazolobenzenesulfonamides which can be usedfor treating neurodegenerative pathologies, such as Alzheimer's disease.JP 7149745 A2 and JP 7149746 A2 both describe 2-aminothiazolederivatives as esterase inhibitors. Nothing is disclosed aboutinhibiting 11βHSD1. JP 7309757 A2 relates to treating Alzheimer'sdisease using N-(5-nitro-2-thiazolyl)benzenesulfonamides. JP 3173876 A2presents preparation of diphenylthiazoles. These compounds are used asanti-inflammatories, analgesics, anti-allergy agents, uric acidaccelerators and blood platelet aggregation inhibitors. EP 0 790 057 A1discloses an antibacterial or bactericide comprising a 2-aminothiazolederivative. U.S. Pat. No. 2,362,087 describes the preparation ofthiazolobenzenesulfonamides, such as2-bromobenzenesulfonamido-4-methylthiazole. Nothing is disclosed aboutinhibiting 11βHSD1 and no therapeutic use of such substances isdisclosed.

However, none of the above disclosures discloses the compounds accordingto the present invention, or their use for the treatment of diabetes,obesity, glaucoma, osteoporosis, cognitive disorders, immune disorders,and depression.

Consequently, there is a need of new compounds that are useful in thetreatment of diabetes, obesity, glaucoma, osteoporosis, cognitivedisorders, immune disorders, and depression.

DISCLOSURE OF THE INVENTION

The compounds according to the present invention solve the aboveproblems and embraces a novel class of compounds which has beendeveloped and which inhibit the human 11-β-hydroxysteroid dehydrogenasetype 1 enzyme (11β-HSD₁), and may therefore be of use in the treatingdisorders such as diabetes, obesity, glaucoma, osteoporosis, cognitivedisorders; immune disorders, and depression.

One object of the present invention is compound of formula (I)

wherein

T is

I) thienyl which optional is substituted with at least one halogen, or

II) phenyl substituted with

a) at least one C₂₋₆-alkyl; or

b) at least one C₁₋₆-alkyl and at least one halogen; or

c) at least three halogens;

E is a bond, —CH₂— or —CO—;

L is a bond, —CH₂—, —CHR⁴— or —NR³—;

R³ is H, C₁₋₆-alkyl, C₁₋₆-acyl or —COR⁴;

R⁴ is morpholinyl or C₁₋₆ amido;

R⁶ and R⁷ are independently hydrogen or C₁₋₆-alkyl; and

R⁸ and R⁹ are independently hydrogen or C₁₋₆-alkyl, as well aspharmaceutically acceptable salts, hydrates and solvates thereof.

It is preferred that:

T is

I) thienyl, which is substituted with at least one halogen selected fromchloro and bromo, or

II) phenyl substituted with

a) at least one n-propyl; or

b) at least one methyl and at least one halogen selected from chloro andbromo; or

c) at least three halogens selected from fluoro, bromo and chloro;

E is a bond, —CH₂— or —CO—;

L is a bond, —CH₂—, —CHR⁴— or —NR³—;

R³ is methyl, acetyl or —COR⁴;

R⁴ is morpholinyl or propionamido;

R⁶ and R⁷ are both hydrogen; and

R⁸ and R⁹ are independently hydrogen or methyl.

Specific examples of compounds according to the present invention are:

N-(5-Acetyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)-3-chloro-2-methylbenzenesulfonamide;

2,4-dichloro-6-methyl-N-(5,6,6-trimethyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)benzenesulfonamide;

2,4-dichloro-6-methyl-N-[5-(4-morpholinylcarbonyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl]benzenesulfonamide;

2,4-Dichloro-6-methyl-N-(4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)benzenesulfonamide;

4-Bromo-N-(5,6-dihydro-4H-cyclopenta[d][1,3]thiazol-2-yl)-2,5-difluorobenzenesulfonamide;

2,3,4-Trichloro-N-(5,6-dihydro-4H-cyclopenta[d][1,3]thiazol-2-yl)benzenesulfonamide;

N-(2-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-4,5,6,7-tetrahydro-1,3-benzothiazol-6-yl)propanamide;

2,4-Dichloro-N-5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)-6-methylbenzenesulfonamide;

2,3,4-Trichloro-N-(5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)benzenesulfonamide;

4,5-Dichloro-N-(5,5-dimethyl-7-oxo-4,5,6,7-terahydro-1,3-benzothiazol-2-yl)-2-thiophenesulfonamide;

4-Bromo-5-chloro-N-(5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)-2-thiophenesulfonamide;

3-Bromo-5-chloro-N-(5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)-2-thiophenesulfonamide;

N-(5-Methyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)-4-propylbenzenesulfonamide;

4,5-Dichloro-N-5-methyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)-2-thiophenesulfonamide;

2,4-Dichloro-6-methyl-N-(5-methyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)benzenesulfonamide;and

4-Bromo-2-methyl-N-(5-methyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)benzenesulfonamide.

Another object of the present invention is compound as described abovefor medical use.

The compounds as described above can be prepared by methods comprisingat least one of the following steps:

a) sulfonamide coupling by reacting a 2-aminothiazole with asulfonylchloride in the presence of a base,

b) sulfonamide coupling by reacting a 2-aminothiazole derivative with asulfonylchloride in the presence of a base.

Another object of the present invention is a method for the treatment orprevention of diabetes, syndrome X obesity, glaucoma, hyperlipidemia,hyperglycemia, hyperinsulinemia, osteoporosis, tuberculosis, dementia,depression, virus diseases and inflammatory disorders, said methodcomprising administering to a mammal,

including man, in need of such treatment, an effective amount of acompound having the formula (I)

wherein

T is I) thienyl, which optionally is substituted with halogen, or

-   -   II) phenyl optionally substituted with halogen and/or C₁₋₆alkyl;

E is a bond, —CH₂— or —CO—;

L is a bond, —CH₂—, —CHR⁴— or —NR³—;

R³ is H, C₁₋₆-alkyl, C₁₋₆-acyl or COR⁴;

R⁴ is morpholino or C₁₋₆-amido;

R⁶ and R⁷ are independently hydrogen or C₁₋₆-alkyl; and

R⁸ and R⁹ are independently hydrogen or C₁₋₆-alkyl, as well aspharmaceutically acceptable salts, hydrates and solvates thereof.

These compounds may also be used in the manufacture of a medicament forthe treatment or prevention of diabetes, syndrome X, obesity, glaucoma,hyperlipidemia, hyperglycemia, hyperinsulinemia, osteoporosis,tuberculosis, dementia, depression, virus diseases and inflammatorydisorders.

It is preferred that:

T is

I) thienyl which is substituted with at least one halogen selected fromchloro and bromo, or

II) phenyl, which is substituted with at least one of methyl n-propylfluoro, chloro and bromo;

E is a bond, —CH₂— or —CO—;

L is a bond, —CH₂—, —CHR⁴— or —NR³—;

R³ is methyl, acetyl or —COR⁴;

R⁴ is morpholinyl or propionamido;

R⁶ and R⁷ are both hydrogen; and

R⁸ and R⁹ are independently hydrogen or methyl.

Specific examples of compounds according to the present invention aregiven above.

Another object of the present invention is a pharmaceutical compositioncomprising at least one compound of the formula (I) as defined above,and a pharmaceutically acceptable carrier.

The compounds according to the present invention may be used in severalindications which involve 11-β-hydroxysteroid dehydrogenase type 1enzyme. Thus the compounds according to the present invention may beused against dementia (see WO97/07789), osteoporosis (see Canalis E1996, Mechanisms of glucocorticoid action in bone: implications toglucocorticoid-induced osteoporosis, Journal of Clinical Endocrinologyand Metabolism, 81, 3441-3447) and may also be used disorders in theimmune system (see Franchimont et al, “Inhibition of Th1 immune responseby glucocorticoids: dexamethasone selectively inhibits IL-12-inducedStat 4 phosphorylation in T lymphocytes”, The journal of Immunology2000, Feb. 15, vol 164 (4), pages 1768-74) and also in the above listedindications.

The various terms used, separately and in combinations, in the abovedefinition of the compounds having the formula (I) will be explained.

The term “aryl” in the present description is intended to includearomatic rings (monocyclic or bicyclic) having from 6 to 10 ring carbonatoms, such as phenyl (Ph) and naphthyl, which optionally may besubstituted by C₁₋₆-alkyl. Examples of substituted aryl groups arebenzyl, and 2-methylphenyl.

The term “heteroaryl” means in the present description a monocyclic, bi-or tricyclic aromatic ring system (only one ring need to be aromatic)having from 5 to 14, preferably 5 to 10 ring atoms such as 5, 6, 7, 8, 9or 10 ring atoms (mono- or bicyclic), in which one or more of the ringatoms are other than carbon, such as nitrogen, sulfur, oxygen andselenium. Examples of such heteroaryl rings are pyrrole, imidazole,thiophene, furan, thiazole, isothiazole, thiadiazole, oxazole,isoxazole, oxadiazole, pyridine, pyrazine, pyrimidine, pyridazine,pyrazole, triazole, tetrazole, chroman, isochroman, quinoline,quinoxaline, isoquinoline, phthalazine, cinnoline, quinazoline, indole,isoindole, indoline, isoindoline, benzothiophene, benzofuran,isobenzofuran, benzoxazole, 2,1,3-benzoxadiazole, benzothiazole,2,1,3-benzothiazole, 2,1,3-benzoselenadiazole, benzimidazole, indazole,benzodioxane, indane, 1,2,3,4-tetrahydroquinoline,3,4-dihydro-2H-1,4-benzoxazine, 1,5-naphthyridine, 1,8-naphthyridine,acridine, fenazine and xanthene.

The team “heterocyclic” in the present description is intended toinclude unsaturated as well as partially and fully saturated mono-; bi-and tricyclic rings having from 4 to 14, preferably 4 to 10 ring atoms,such as, for example, the heteroaryl groups mentioned above as well asthe corresponding partially saturated or fully saturated heterocyclicrings. Exemplary saturated heterocyclic rings are azetidine,pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine and1,4-oxazepane.

C₁₋₆-alkyl in the compound of formula (I) according to the presentapplication, which may be straight, branched or cyclic, is preferablyC₁₋₄-alkyl. Exemplary alkyl groups include methyl ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl,isohexyl, and cyclohexyl.

C₂₋₆-alkyl in the compound of formula (I) according to the presentapplication, which may be straight, branched or cyclic, is preferablyC₂₋₄-alkyl. Exemplary alkyl groups include ethyl n-propyl, isopropyl,n-butyl, sec-butyl, tert-butyl pentyl, isopentyl, hexyl, isohexyl, andcyclohexyl.

C₁₋₆-acyl in the compound of formula (I) according to the presentapplication may be saturated or unsaturated and is preferably C₁₋₄-acyl.Exemplary acyl groups include formyl, acetyl, propionyl, butyryl,isobutyryl, valeryl, isovaleryl, butenoyl (e.g. 3-butenoyl), hexenoyl(e.g. 5-hexenoyl).

C₁₋₆-amido, in the compound of formula (I) according to the presentapplication may be saturated or unsaturated and is preferablyC₁₋₄-amido. Exemplary amido groups include formamido, acetamido,propionamido, butyramido, isobutyramido, valeramido, isovaleramido,butenamido (e.g. 3-butenamido), hexenamido (e.g. 5-hexenamido).

The term “halogens” in the present description is intended to includefluorine, chlorine, bromine and iodine.

With the expression mono- or di-substituted is meant in the presentdescription that the functionalities in question may be substituted withindependently H, C₁₋₆-acyl, C₁₋₆-alkenyl, C₁₋₆-(cyclo)alkyl, aryl,pyridylmethyl, or heterocyclic rings e.g. azetidine, pyrrolidine,piperidine, piperazine, morpholine and thiomorpholine, whichheterocyclic rings optionally may be substituted with C₁₋₆-alkyl.

The term “prodrug forms” in the present description means apharmacologically acceptable derivative, such as an ester or an amide,which derivative is biotransformed in the body to form the active drug(see Goodman and Gilman's, The Pharmacological basis of Therapeutics,8^(th) ed., McGraw-Hill, Int. Ed. 1992, “Biotransformation of Drugs, p.13-15).

“Pharmaceutically acceptable” means in the present description beinguseful in preparing a pharmaceutical composition that is generally safe,non-toxic and neither biologically nor otherwise undesirable andincludes being useful for veterinary use as well as human pharmaceuticaluse.

“Pharmaceutically acceptable salts” mean in the present descriptionsalts which are pharmaceutically acceptable, as defined above, and whichpossess the desired pharmacological activity. Such salts include acidaddition salts formed with organic and inorganic acids, such as hydrogenchloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoricacid, acetic acid, glycolic acid, maleic acid, malonic acid, oxalicacid, methanesulfonic acid, trifluoroacetic acid, fumaric acid, succinicacid, tartaric acid, citric acid, benzoic acid, ascorbic acid and thelike. Base addition salts may be formed with organic and inorganicbases, such as sodium, ammonia, potassium, calcium, ethanolamine,diethanolamine, N-methylglucamine, choline and the like.

Pharmaceutical compositions according to the present invention contain apharmaceutically acceptable carrier together with at least one of thecompounds comprising the formula (I) as described herein above,dissolved or dispersed therein as an active, antimicrobial ingredient.In a preferred embodiment, the therapeutic composition is notimmunogenic when administered to a human patient for therapeuticpurposes, unless that purpose is to induce an immune response.

The preparation of a pharmacological composition that contains activeingredients dissolved or dispersed therein is well understood in theart. Typically such compositions are prepared as sterile injectableseither as liquid solutions or suspensions, aqueous or non-aqueous,however, solid forms suitable for solution, or suspensions, in liquidprior to use can also be prepared. The preparation can also beemulsified.

The active ingredient may be mixed with excipients, which arepharmaceutically acceptable and compatible with the active ingredientand in amounts suitable for use in the therapeutic methods describedherein. Suitable excipients are, for example, water, saline, dextrose,glycerol, ethanol or the like and combinations thereof. In addition, ifdesired, the composition may contain minor amounts of auxiliarysubstances such as wetting or emulsifying agents, pH buffering agentsand the like which enhance the effectiveness of the active ingredient.Adjuvants may also be present in the composition.

Pharmaceutically acceptable carriers are well known in the art.Exemplary of liquid carriers are sterile aqueous solutions that containno materials in addition to the active ingredients and water, or containa buffer such as sodium phosphate at physiological pH value,physiological saline or both, such as phosphate-buffered saline. Stillfurther, aqueous carriers can contain more than one buffer salt, as wellas salts such as sodium and potassium chlorides, dextrose, propyleneglycol, polyethylene glycol and other solutes.

Liquid compositions can also contain liquid phases in addition to and tothe exclusion of water. Exemplary of such additional liquid phases areglycerine, vegetable oils such as cottonseed oil, organic esters such asethyl oleate, and water-oil emulsions.

The pharmaceutical composition according to one of the preferredembodiments of the present invention comprising compounds comprising theformula (I), may include pharmaceutically acceptable salts of thatcomponent therein as set out above. Pharmaceutically acceptable saltsinclude the acid addition salts (formed with the free amino groups ofthe polypeptide) that are formed with inorganic acids such as, forexample, hydrochloric or phosphoric acids, or such organic acids asacetic acid, tartaric acid, mandelic acid and the like. Salts formedwith the free carboxyl groups can also be derived from inorganic basessuch as, for example, sodium, potassium, ammonium, calcium or ferrichydroxides, and such organic bases as isopropylamine, trimethylamine,2-ethylamino ethanol, histidine, procaine and the like.

The preparations according to the preferred embodiments may beadministered orally, topically, intraperitoneally, intraarticularly,intracranially, intradermally, intramuscularly, intraoculary,intrathecally, intravenously, subcutaneously. Other routes which areknown for the skilled person in the art are thinkable.

The orally administrable compositions according to the present inventionmay be in the form of tablets, capsules, powders, granules, lozenges,liquid or gel preparations, such as oral, topical or sterile parenteralsolutions or suspensions. Tablets and capsules for oral administrationmay be in unit dose presentation form and may contain conventionalexcipients such as binding agents, for example syrup, acacia, gelatin,sorbitol, traganath or polyvinyl-pyrrolidone; fillers e.g. lactose,sugar, maize-starch, calcium phosphate, sorbitol or glycine; tablettinglubricant e.g. magnesium stearate, talc, polyethylene glycol or silica;disintegrants e.g. potato starch, or acceptable wetting agents such assodium lauryl sulfate. The tablets may be coated according to methodswell known in normal pharmaceutical practice. Oral liquid preparationsmay be in the form of e.g. aqueous or oily suspensions, solutions,emulsions, syrups or elixirs or may be presented as a dry product forreconstitution with water or other suitable vehicle before use. Suchliquid preparations may contain conventional additives such assuspending agents, e.g. sorbitol, syrup, methyl cellulose, glucosesyrup, gelatin hydrogenated edible fats; emulsifying agents e.g.lecithin, sorbitan monooleate or acacia, non-aqueous vehicles (which mayinclude edible oils), e.g. almond oil, fractionated coconut oil, oilyesters such as glycerine, propylene glycol, or ethyl alcohol;preservatives e.g. methyl or propyl p-hydroxybenzoate or sorbic acid,and if desired conventional flavouring or colouring agents.

A pharmaceutical composition according to the present invention, maycomprise typically an amount of at least 0.1 weight percent of compoundcomprising the formula (I) per weight of total therapeutic composition.A weight percent is a ratio by weight of total composition. Thus, forexample, 0.1 weight percent is 0.1 grams of compound comprising theformula (I) per 100 grams of total composition. A suitable daily oraldose for a mammal, preferably a human being, may vary widely dependingon the condition of the patient. However a dose of compound comprisingthe formula (I) of about 0.1 to 300 mg/kg body weight may beappropriate.

The compositions according to the present invention may also be usedveterinarily and thus they may comprise a veterinarily acceptableexcipient or carrier.

The compounds of the present invention in labelled form, e.g.isotopically labelled, may be used as a diagnostic agent.

The compounds of the formula (I) above may be prepared by, or in analogywith, conventional methods, and especially according to or in analogywith the following methods. Further, the pharmacology in-vitro wasstudied using the following reagents and methods.

All publications mentioned herein are hereby incorporated by reference.By the expression “comprising” we understand including but not limitedto. Thus, other non-mentioned substances, additives or carriers may bepresent.

The invention will now be described in reference to the followingFigures and Examples. These Figures and Examples are not to be regardedas limiting the scope of the present invention, but shall only serve inan illustrative manner.

Experimental Methods

Scintillation Proximity Assay

[1, 2(n)-³H]-cortisone was purchased from Amersham Pharmacia Biotech.Anti-cortisol monoclonal mouse antibody, clone 6D6.7 was obtained fromImmunotech and Scintillation proximity assay (SPA) beads coated withmonoclonal antimouse antibodies were from Amersham Pharmacia Biotech.NADPH, tetrasodium salt was from Calbiochem and glucose-6-phosphate(G-6-P) was supplied by Sigma. The human 11-β-hydroxysteroiddehydrogenase type-1 enzyme (11-β-HSD₁) was expressed in Pichiapastoris. 18-β-glycyrrhetinic acid (GA) was obtained from Sigma. Theserial dilutions of the compounds were performed on a Tecan Genesis RSP150. Compounds to be tested were dissolved in DMSO (1 mM) and diluted in50 mM Tris-HCl, pH 7.2 containing 1 mM EDTA.

The multiplication of plates was done on a WallacQuadra. The amount ofthe product [³H]-cortisol, bound to the beads was determined in aPackard, Top Count microplate liquid scintillation counter.

The 11-β-HSD₁ enzyme assay was carried out in 96 well microtiter plates(Packard, Optiplate) in a total well volume of 220 μL and contained 30mM Tris-HCl, pH 7.2 with 1 mM EDTA, a substrate mixture tritiatedCortisone/NADPH (175 nM/181 μM, G-6-P (1 mM) and inhibitors in serialdilutions (9 to 0.15 μM). Reactions were initiated by the addition ofhuman 11-β-HSD₁, either as Pichia pastoris cell homogenate or microsomesprepared from Pichia pastoris (the final amount of enzyme used wasvaried between 0.057 to 0.11 mg/mL). Following mixing, the plates wereshaken for 30 to 45 minutes at room temperature. The reactions wereterminated with 10 μL 1 mM GA stop solution. Monoclonal mouse antibodywas then added (10 μL of 4 μM followed by 100 μL of SPA beads (suspendedaccording to the manufacturers instructions). Appropriate controls wereset up by omitting the 11-β-HSD₁ to obtain the non-specific binding(NSB) value.

The plates were covered with plastic film and incubated on a shaker for30 minutes, at room temperature, before counting. The amount of[³H]-cortisol, bound to the beads was determined in a microplate liquidscintillation counter.

The calculation of the K_(i) values for the inhibitors was performed byuse of Activity Base. The K_(i) value is calculated from IC₅₀ and theK_(m) value is calculated using the Cheng Prushoff equation (withreversible inhibition that follows the Michaelis-Menten equation):K_(i)=IC₅₀(1+[S]/K_(m)) [Cheng, Y. C.; Prushoff, W. H. Biochem.Pharmacol. 1973, 22, 3099-3108]. The IC₅₀ is measured experimentally inan assay wherein the decrease of the turnover of cortisone to cortisolis dependent on the inhibition potential of each substance. The Kivalues of the compounds of the present invention for the 11-β-HSD1enzyme lie typically between about 10 nM and about 10 μM. Illustrativeof the invention, the following Ki values have been determined in thehuman 11-β-HSD1 enzyme assay (see Table 1): TABLE 1 Ki values determinedin the human 11-β-HSD1 enzyme assay. Compound of Example K_(i) (nM) 8 2816 227

Compound Preparation

General:

For preparative straight phase HPLC purification a Phenomenex column(250×21.1 mm, 10 μm) was used on a Gilson system eluting with ethanol inchloroform (gradient from 0-10% in 10 min) with a flow of 20 mL/min.Column chromatography was performed on silica using Silica gel 60(230-400 mesh), Merck. Melting points were determined on a Gallenkampapparatus. Elemental analyses were recorded using a Vario EL instrument.HPLC analyses were performed using a Hypersil Elite column (150×4.6 mm,3 μ) with a flow of 3 mL/min on a Waters 600E system with monitoring at254 nm. Reverse phase preparative HPLC was carried out on a 100×21.2 mm,5 μ Hypersil Elite column eluting with a gradient of 5% ACN in 95% waterto 95% ACN in 5% water (0.2% TFA buffer) over 10 mins at a flow rate of20 mL/min with the UV detector set at 254 nm. Thin layer chromatographywas carried out using pre-coated silica gel F-254 plates (thickness 0.25mm). Electrospray MS spectra were obtained on a Micromass platform LCMSspectrometer. Crude, worked up compounds were purified by flash columnchromatography using pre packed silica SPE columns (10 g silica) on anIsco Foxy 200 Combiflash system, and a grade of 16.67% ethyl acetate inhexane increasing incrementally to 100% ethyl acetate.

List of Abbreviations

DCM=dichloromethane

DMAP=4-dimethylaminopyridine

DMF=dimethylformamide

DMSO=dimethyl sulfoxide

EDTA=ethylenediaminetetraacetic acid

Sulfonamide Couplings:

Method A:

1 Eq of the 2-aminothiazole was dissolved in pyridine (0.5 M solution).The sulfonyl chloride (1.2 eq) was added and the reaction mixture wasstirred at ambient temperature under nitrogen atmosphere for 15 h. Thereaction mixture was poured into aqueous HCl (1 M). If the productprecipitated it was collected on a filter and washed with aqueous HCl (1M) and recrystallised from ethanol. In case an oil was obtained, thecrude was extracted with DCM and worked up and purified using standardprocedures.

Method B:

A solution of the 2-aminothiazole derivative (1 eq), triethylamine (2eq) and DMAP (1 eq) in DMF (1 M) and DCM (0.225 M) was dispensed into areaction vial. The sulfonyl chloride (1.2 eq) was dissolved in DCM (0.33M) and added. The reaction mixtures were kept at room temperature overnight. The mixture was then added to petroleum ether (10 times reactionvolume). After some hours in refrigerator the supernatants were decantedand (a portion of) the residual materials were dissolved inDMSO-methanol-acetic acid (300 μL+500 μL+50 μl) and purified bypreparative LCMS (acetonitrile-water gradients). The purest fractionswere collected and lyophilized. Alternatively, the crude was isolatedusing extractive work-up and purified using standard procedures.

EXAMPLES

The following specific compounds were synthesizd. The commerciallyavailable compounds thus only form embodiments, as indicated earlier inthe description, as pharmaceutical compositions and use of saidcompounds as set out in the appended set of claims.

Example 1 [210P]N-(5-Acetyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)-3-chloro-2-methylbenzenesulfonamide

N-Acetyl-4-piperidone (7.05 g, 0.05 mol) in acetic acid (35 mL) wastreated dropwise with bromine (8.0 g, 0.05 mol) in acetic acid (10 mL)at room temperature. After 4 h, the formed precipitate was collected ona filter, washed with diethyl ether and air-dried. This crudeintermediate (3.01 g) was dissolved in ethanol (20 mL) and after theaddition of thiourea (0.76 g, 10.0 mmol) the reaction mixture wasrefluxed for 4 h. The solvent was removed in vacuo. Water (20 mL) wasadded and the pH was adjusted to 9. Extraction with DCM, drying (sodiumsulfate) and removal of the organic phase gave 1.1 g of a crude product.Purification by flash chromatography on silica gel gave 202 mg (10%) of5-acetyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-ylamine. Thiscompound was sulfonylated with 3-chloro-2-methylbenzene sulfonylchloride (234 mg, 1.02 mmol) in pyridine according to METHOD A. Afterworkup, the final product was crystallised from methanol to afford 75 mg(%) of white crystals: ¹H NMR (DMSO-d₆, 70° C.) δ 2.05 (s, 3H), 2.66 (s,3H), 3.09 (m, 2H), 3.69 (m, 2H), 4.38 (m, 2H), 7.37 (t, 1H), 7.64 (d,1H), 7.91 (d, 1H), 12.53 (br s, NH).

Example 2 [211A]2,4dichloro-6methyl-N-(5,6,6-trimethyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)benzenesulfonamide

The title compound was prepared from5,6,6-trimethyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,7-c]pyridin-2-amine(45 mg, 0.23 mmol) as described in the synthetic METHOD B to give awhite solid (13.0 mg) with purity>90%. MS (pos) m/z 420.1, 422.1.

Example 3 [212A]2,4-dichloro-6-methyl-N-[5-(4-morpholinylcarbonyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl]benzenesulfonamide

The title compound was prepared from5-(4-morpholinylcarbonyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-amine(39 mg, 0.15 mmol) as described in the synthetic METHOD B to give ayellow solid (15.4 mg) with purity>90%. MS (pos) m/z 491.1, 493.1.

Example 4 [234A]2,4Dichloro-6-methyl-N-(4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)benzenesulfonamide

The title compound was prepared from4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine as described in thesynthetic METHOD B to give a white solid (10.8 mg) with purity>90%. MS(pos) m/z 377.1, 379.1.

Example 5 [234B]4-Bromo-N-(5,6-dihydro-4H-cyclopenta[d][1,3]thiazol-2-yl)-2,5-difluorobenzenesulfonamide

The title compound was prepared from2-amino-5,6-dihydro-4H-cyclopentathiazole hydrochloride (48 mg) and4-bromo-2,5-difluorobenzenesulfonyl chloride (79 mg) as described in thesynthetic METHOD B to give a yellow solid (2.5 mg) with purity>80%. MS(pos) m/z 395.2, 397.2; MS (neg) m/z 393.4, 395.4.

Example 6 [234C]2,3,4-Trichloro-N-(5,6-dihydro-4H-cyclopenta[d][1,3]thiazol-2-yl)benzenesulfonamide

The title compound was prepared from2-amino-5,6-dihydro-4H-cyclopentathiazole hydrochloride (48 mg) and2,3,4-trichlorobenzenesulfonyl chloride (76 mg) as described in thesynthetic METHOD B to give a yellow solid (4.5 mg): MS (pos) m/z 383.3,385.3, 387.3; MS (neg) m/z 381.4, 383.4, 385.4.

Example 7 [235A]N-2-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-4,5,6,7-tetrahydro-1,3-benzothiazol-6-yl)propanamide

The title compound was prepared fromN-(2-amino-4,5,6,7-tetrahydro-1,3-benzothiazol-6-yl)propanamide (47 mg,0.21 mmol) and 2,4-dichloro-6-methylbenzenesulfonyl chloride asdescribed in the synthetic METHOD B to give a white solid (20.3 mg) withpurity>90%. MS (pos) m/z 448.1, 450.1.

Example 8 [236A]2,4-Dichloro-N-(5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)-6-methylbenzenesulfonamide

The title compound was prepared from2-amino-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one hydrobromideand 2,4-dichloro-6-methylbenzenesulfonyl chloride as described in thesynthetic METHOD B to give a white-yellow solid (26 mg) with purity>90%:MS (pos) m/z 419.1, 421.1; HRMS m/z 417.9979 (calc. of monoisotopic massfor C₁₆H₁₆Cl₂N₂O₃S₂ gives 411.9979).

Example 9 [236B]2,3,4-Trichloro-N-(5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)benzenesulfonamide

The title compound was prepared from2-amino-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one (53 mg) and2,3,4-trichlorobenzenesulfonyl chloride (76 mg) as described in thesynthetic METHOD B to give a white solid (47.2 mg) with purity>90%: MS(pos) m/z 439.3, 441.3; HRMS m/z 437.9451 (calc. of monoisotopic massfor C₁₅ H₁₃ Cl₃ N₂ O₃ S₂ gives 437.9433).

Example 10 [236C]4,5-Dichloro-N-(5,5dimethyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)-2-thiophenesulfonamide

The title compound was prepared from2-amino-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one (53 mg) and2,3-dichlorothiophene-5-sulfonyl chloride (68 mg) as described in thesynthetic METHOD B to give a white-yellow solid (36.8 mg) withpurity>90%: MS (pos) m/z 411.3, 413.3.

Example 11 [236D]4-Bromo-5-chloro-N-(5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)-2-thiophenesulfonamide

The title compound was prepared from2-amino-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one (53 mg) and4-bromo-5-chlorothiophene-2-sulfonyl chloride (80 mg) as described inthe synthetic METHOD B to give a white-yellow solid (47.1 mg) withpurity>90%: MS (pos) m/z 455.2, 457.2.

Example 12 [236E]3-Bromo-5-chloro-N-(5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)-2-thiophenesulfonamide

The title compound was prepared from2-amino-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one (53 mg) and3-bromo-5-chlorothiophene-2-sulfonyl chloride (80 mg) as described inthe synthetic method to give a white solid (62.2 mg) with purity>90%: MS(pos) m/z 455.2, 457.2.

Example 13 [236F]N-(5Methyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)-4-propylbenzenesulfonamide

The title compound was prepared from2-amino-5-methyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one (49 mg) and4-n-propylbenzenesulfonyl chloride (59 mg) as described in the syntheticMETHOD B to give a white solid (51.2 mg) with purity>90%: MS (neg) m/z363.6; HRMS m/z 364.0911 (calc. of monoisotopic mass for C₁₇ H₂₀ Cl₅ N₂O₃ S₂ gives 364.0915).

Example 14 [236G]4,5-Dichloro-N-(5-methyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)-2-thiophenesulfonamide

The title compound was2-amino-5-methyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one (49 mg) and2,3-dichlorothiophene-5-sulfonyl chloride (68 mg) as described in thesynthetic METHOD B to give a white solid (34.2 mg) with purity>90%: MS(pos) m/z 397.2, 399.2; MS (neg) m/z 395.2, 397.2.

Example 15 [236H]2,4-Dichloro-6-methyl-N-(5-methyl-7-oxo-4,5,9,6,7-tetrahydro-1,3-benzothiazol-2-yl)benzenesulfonamide

The title compound was2-amino-5-methyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one (49 mg) and2,4-dichloro-6-methylbenzenesulfonyl chloride (70 mg) as described inthe synthetic METHOD B to give a white solid (39.3 mg) with purity>90%:MS (pos) m/z 405.4, 407.4; MS (neg) m/z 403.4, 405.3.

Example 16 [236I]4-Bromo-2-methyl-N-(5-methyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)benzenesulfonamide

The title compound was2-amino-5-methyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one (49 mg) and4-bromo-2-methylbenzenesulfonyl chloride (73 mg) as described in thesynthetic METHOD B to give a white solid (34.4 mg) with purity>90%: MS(pos) m/z 415.4, 417.4; Ms (neg) m/z 413.4, 415.4.

Various embodiments of the present invention have been described abovebut a person skilled in the art realizes further minor alterations whichwould fall into the scope of the present invention. The breadth andscope of the present invention should not be limited by any of theabove-described exemplary embodiments, but should be defined only inaccordance with the following claims and their equivalents.

1-12. (canceled)
 13. A method for the treatment or prevention ofosteoporosis, cognitive impairment, depression, virus diseases andinflammatory disorders and to achieve immuno-modulation, said methodcomprising administering to a mammal, including man, in need of suchtreatment, an effective amount of a compound having the formula (I)

wherein T is I) thienyl, which optionally is substituted with at leastone halogen or II) phenyl substituted with a) at least one of C₂₋₆alkyl; or b) at least one C₁₋₆ alkyl and at least one halogen; or c) atleast three halogens; E is a bond, —CH₂— or —CO—; L is a bond, —CH₂—,—CHR⁴— or —NR³—; R³ is H, C₁₋₆ alkyl, C₁₋₆ acyl or —COR⁴—; R⁴ ismorpholinyl or C₁₋₆ amido; R⁶ and R⁷ are independently hydrogen or C₁₋₆alkyl and R⁸ and R⁹ are independently hydrogen or C₁₋₆ alkyl, as well aspharmaceutically acceptable salts, hydrates and solvates thereof.
 14. Amethod according to claim 13, wherein the immuno-modulation is achievedby the treatment or prevention of tuberculosis, lepra and psorasis. 15.A method according to claim 13, wherein T is I) thienyl, whichoptionally is substituted with at least one halogen selected from chloroand bromo, or II) phenyl substituted with a) at least one n-propyl; orb) at least one methyl and at least one halogen selected from chloro andbromo; or c) at least three halogens selected from fluoro, bromo andchloro; E is a bond, —CH₂— —CO—; L is a bond, —CH₂—, —CHR⁴— or —NR³—; R³is methyl, acetyl or —COR⁴; R⁴ is morpholinyl or propionamido; R⁶ and R⁷are both hydrogen; and R⁸ and R⁹ are independently hydrogen or methyl.16. A method according to claim 13, wherein the compound is selectedfrom the group of:N-(5-Acetyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)-3-chloro-2-methylbenzenesulfonamide;2,4-dichloro-6-methyl-N-(5,6,6-trimethyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-yl)benzenesulfonamide;2,4-dichloro-6-methyl-N-[5-(4-morpholinylcarbonyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl]benzenesulfonamide;2,4-Dichloro-6-methyl-N-(4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)benzenesulfonamide;4-Bromo-N-(5,6-dihydro-4H-cyclopenta[d][1,3]thiazol-2-yl)-2,5-difluorobenzenesulfonamide;2,3,4-Trichloro-N-(5,6-dihydro-4H-cyclopenta[d][1,3]thiazol-2-yl)benzenesulfonamide;N-(2-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-4,5,6,7-tetrahydro-1,3-benzothiazol-6-yl)propanamide;2,4-Dichloro-N-(5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)-6-methylbenzenesulfonamide;2,3,4-Trichloro-N-(5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)benzenesulfonamide;4,5-Dichloro-N-(5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)-2-thiophenesulfonamide;4-Bromo-5-chloro-N-(5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)-2-thiophenesulfonamide;3-Bromo-5-chloro-N-(5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)-2-thiophenesulfonamide;N-(5-Methyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)-4-propylbenzenesulfonamide;4,5-Dichloro-N-(5-methyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)-2-thiophenesulfonamide;2,4-Dichloro-6-methyl-N-(5-methyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)benzenesulfonamide;and4-Bromo-2-methyl-N-(5-methyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)benzenesulfonamide,and pharmaceutically acceptable salts, hydrates and solvates thereof.